NM_001077365.2(POMT1):c.2101dup (p.Asp701fs) AND Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003411.17

Allele description [Variation Report for NM_001077365.2(POMT1):c.2101dup (p.Asp701fs)]

NM_001077365.2(POMT1):c.2101dup (p.Asp701fs)

Gene:

POMT1:protein O-mannosyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

9q34.13

Genomic location:

Preferred name:

NM_001077365.2(POMT1):c.2101dup (p.Asp701fs)

Other names:

NM_001077365.2(POMT1):c.2101dup; p.Asp701fs

HGVS:

NC_000009.12:g.131523029dup
NG_008896.1:g.25128dup
NM_001077365.2:c.2101dupMANE SELECT
NM_001077366.2:c.1939dup
NM_001136113.2:c.2101dup
NM_001136114.2:c.1750dup
NM_001353193.2:c.2167dup
NM_001353194.2:c.1939dup
NM_001353195.2:c.1750dup
NM_001353196.2:c.2011dup
NM_001353197.2:c.2005dup
NM_001353198.2:c.2005dup
NM_001353199.2:c.1816dup
NM_001353200.2:c.1645dup
NM_001374689.1:c.2089dup
NM_001374690.1:c.1882dup
NM_001374691.1:c.1750dup
NM_001374692.1:c.1750dup
NM_001374693.1:c.1750dup
NM_001374695.1:c.1711dup
NM_007171.4:c.2167dup
NP_001070833.1:p.Asp701fs
NP_001070834.1:p.Asp647fs
NP_001129585.1:p.Asp701fs
NP_001129586.1:p.Asp584fs
NP_001340122.2:p.Asp723fs
NP_001340123.1:p.Asp647fs
NP_001340124.1:p.Asp584fs
NP_001340125.1:p.Asp671fs
NP_001340126.2:p.Asp669fs
NP_001340127.2:p.Asp669fs
NP_001340128.2:p.Asp606fs
NP_001340129.1:p.Asp549fs
NP_001361618.1:p.Asp697fs
NP_001361619.1:p.Asp628fs
NP_001361620.1:p.Asp584fs
NP_001361621.1:p.Asp584fs
NP_001361622.1:p.Asp584fs
NP_001361624.1:p.Asp571fs
NP_009102.3:p.Asp723fs
NP_009102.4:p.Asp723fs
LRG_842t1:c.2167dup
LRG_842t2:c.2101dup
LRG_842p1:p.Asp723fs
LRG_842p2:p.Asp701fs
NC_000009.11:g.134398412_134398413insG
NC_000009.11:g.134398416dup
NM_007171.3:c.2167dup
NM_007171.3:c.2167dupG
NM_007171.4:c.2167dupG
NR_148391.2:n.2135dup
NR_148392.2:n.2353dup
NR_148393.2:n.2274dup
NR_148394.2:n.2028dup
NR_148395.2:n.2426dup
NR_148396.2:n.2060dup
NR_148397.2:n.2185dup
NR_148398.2:n.2140dup
NR_148399.2:n.2666dup
NR_148400.2:n.2265dup
p.D723GfsX8

Protein change:

D549fs

Links:

OMIM: 607423.0018; dbSNP: rs398124245

NCBI 1000 Genomes Browser:

rs398124245

Molecular consequence:

NM_001077365.2:c.2101dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001077366.2:c.1939dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001136113.2:c.2101dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001136114.2:c.1750dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353193.2:c.2167dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353194.2:c.1939dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353195.2:c.1750dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353196.2:c.2011dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353197.2:c.2005dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353198.2:c.2005dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353199.2:c.1816dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001353200.2:c.1645dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374689.1:c.2089dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374690.1:c.1882dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374691.1:c.1750dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374692.1:c.1750dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374693.1:c.1750dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001374695.1:c.1711dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_007171.4:c.2167dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_148391.2:n.2135dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148392.2:n.2353dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148393.2:n.2274dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148394.2:n.2028dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148395.2:n.2426dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148396.2:n.2060dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148397.2:n.2185dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148398.2:n.2140dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148399.2:n.2666dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148400.2:n.2265dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 (MDDGA1)
Synonyms:: Hydrocephalus, agyria and retinal dysplasia; Hard +/- E syndrome; Warburg syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009364; MedGen: C4284790; Orphanet: 588; Orphanet: 899; OMIM: 236670

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023569	OMIM	no assertion criteria provided	Pathogenic (May 26, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000538056	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 24, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001366755	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001426602	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008
SCV004206032	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study.

Mercuri E, Messina S, Bruno C, Mora M, Pegoraro E, Comi GP, D'Amico A, Aiello C, Biancheri R, Berardinelli A, Boffi P, Cassandrini D, Laverda A, Moggio M, Morandi L, Moroni I, Pane M, Pezzani R, Pichiecchio A, Pini A, Minetti C, Mongini T, et al.

Neurology. 2009 May 26;72(21):1802-9. doi: 10.1212/01.wnl.0000346518.68110.60. Epub 2009 Mar 18. Erratum in: Neurology. 2019 Aug 20;93(8):371. doi: 10.1212/WNL.0000000000007479.

PubMed [citation]

PMID:: 19299310

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]

PMID:: 32860008
PMCID:: PMC7852664

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000023569.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the 1-bp duplication in the POMT1 gene (2167dupG) that was found in compound heterozygous state in a patient with muscle-eye-brain disease (MDDGA1; 236670) by Mercuri et al. (2009), see 607423.0017.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538056.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.2167dupG (p.Asp723Glyfs*730) frameshift variant in the POMT1 gene has been previously reported as homozygous (Wallace SE et al., 2014; van Reeuwijk J et al., 2006) as well as compound heterozygous (BeltrÃ¡n-Valero de BernabÃ© D et al., 2002; Wallace SE et al., 2014) in patients who were diagnosed with WWS. Functional studies using a skin biopsy from a WWS patient, who was heterozygous for variant, showed that the protein's molecular weight and binding to the basement membrane ligand, laminin were all affected. Furthermore, immunofluorescence staining of a muscle biopsy from a patient, who was homozygous for this variant, showed almost complete absence of Î±-dystroglycan expression (Wallace SE et al., 2014). The frequency of this variant is absent in the 1000Genome and Exome Sequencing Project databases and is very low in ExAC (<0.1%). Finally, reputable clinical databases have classified this variant as Pathogenic. In summary, the evidence meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366755.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Pathogenic. This variant was inherited from a parent.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV001426602.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004206032.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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